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Large Sequencing Study Hints At Splicing Gene Defects in Subset of CLL Cases

NEW YORK (GenomeWeb News) – A genome and exome sequencing study of 91 individuals with chronic lymphocytic leukemia has uncovered CLL-associated mutations in genes and pathways known to contribute to the disease as well as others not suspected previously, including components of the messenger RNA splicing system.

"Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia," researchers reported in the early, online version of the New England Journal of Medicine yesterday.

A group led by investigators at the Dana-Farber Cancer Institute and the Broad Institute sequenced the exomes of matched tumor-normal samples from 88 individuals with CLL and did whole-genome sequencing on three matched CLL tumor-normal pairs. Four of the nine genes that were most frequently mutated in the genomes and exomes had been tied to CLL or related conditions in the past, they reported, while the remaining five genes had not.

Among the newly identified gene suspects was a spliceosome component coding gene called SF3B1, which was frequently mutated in tumors with other genetic features that often correspond with poor outcomes. Based on this pattern, those involved in the study speculated that alterations affecting gene splicing may be crucial in a subset of CLL cases.

"We have identified a new cancer pathway — aberrant RNA splicing — that has been underappreciated," co-senior author Catherine Wu, a medical oncology researcher at Dana-Farber who is also affiliated with the institute's Cancer Vaccine Center, said in a statement.

In addition to their new NEJM paper the team presented findings from the study at the American Society of Hematology's annual meeting in San Diego yesterday.

Although CLL is a common form of leukemia, Wu and her colleagues explained, its genetic heterogeneity makes it difficult to predict how it will affect different individuals, with some CLL patients surviving several years and others progressing to fatal forms of the disease very rapidly.

"Whereas the course of disease is indolent in some patients, it is steadily progressive in approximately half of patients, leading to substantial morbidity and mortality," they wrote.

In an effort to learn more about CLL biology and track down new prognostic markers for the disease, the researchers used the Illumina GAII to sequence three CLL genomes to an average depth of about 38 times and matched normal genomes to 33 times depth, on average.

The same sequencing platform was also used to generate 132 times coverage of 88 CLL exomes and 146 times average exome coverage for corresponding normal samples.

The team's analyses of the more than 1,800 non-synonymous mutations found in protein-coding sequences from these samples pointed to nine genes that were altered most often.

These included four known cancer or CLL-associated genes — TP53, ATM, MYD88 and NOTCH1 — that were each mutated in between 4 percent and 15 percent of CLL patients tested.

The researchers also found five recurrently mutated genes that had not been implicated in CLL in the past: FBXW7, DDX3X, MAPK1, ZMYM3, and SF3B1, which was mutated in 15 percent of those tested.

The researchers further verified the three most common specific gene changes from the discovery set, which affected the SF3B1, MYD88, or NOTCH1 genes, by testing 101 more CLL and matched normal samples.

Among the pathways affected were those influencing DNA damage repair, cell cycle control, Notch signaling, Wnt signaling, and inflammation. Notably, the team also detected recurrent mutations in genes contributing to RNA splicing and processing activities, including SF3B1, the second most frequently mutated gene after TP53.

Moreover, researchers reported, many of the tumors containing SF3B1 mutations also harbored chromosome 11 deletions that have previously been associated with aggressive forms of CLL and poor patient outcomes. Even in some CLL tumors without the chromosome 11 deletion, the group's results suggest SF3B1 mutations may be tied to more aggressive form of the disease, perhaps due to alterations in the splicing of other cancer-related genes.

"Our results suggest that SF3B1 mutations lead to mistakes in the splicing of … transcripts that affect the pathogenesis of chronic lymphocytic leukemia," the study authors noted. "Ongoing studies will focus on determining how mutations in SF3B1 alter its function in the processing of critical mRNAs."

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